Formulations that can be administered directly to the mucous membrane, such as nasal formulations for the treatment of allergic rhinitis and ophthalmic formulations for the treatment of dry eyes, have been developed to enhance absorption efficiency and pharmacological efficacy of drugs. In these formulations for administration to the mucous membrane an aqueous base is used to avoid irritation to the tissues. Since active ingredients are generally only slightly soluble in the aqueous base, they are often used in form of an aqueous suspension. In addition, aqueous formulations generally contain antiseptics and/or preservatives to inhibit bacterial growth. The use of these antiseptics and/or preservatives in drugs that are used over a long period of time is not preferable in terms of adverse drug reactions to the mucous tissues. Accordingly, safer antiseptics and preservatives have been developed and formulations containing no antiseptics or preservatives have been proposed.
As a method for obtaining so-called sterile formulations that contain no antiseptics or preservatives, sterilization, for example, autoclave sterilization, radiation sterilization, and sterilization by filtration are generally utilized. Various problems occur, however, when these sterilization methods are to be simply applied to manufacturing of an aqueous suspension.
Aqueous suspensions generally contain, as an ingredient, a water soluble or water swellable polymer as a dispersant for dispersing a water insoluble or slightly water soluble active ingredient homogeneously over a long period of time. Thus, when an aqueous suspension is attempted to be obtained by sterilization, for example, autoclave sterilization, radiation sterilization or sterilization by filtration, the structure of these dispersants is destroyed so that problems of safety and long-term dispersion stability of the suspension occur. In this respect, a method in which autoclave sterilization is performed under conditions where salt is contained at a saturation concentration or higher followed by dilution to obtain a sterile aqueous suspension (U.S. Pat. No. 3,962,430) and a method in which an aqueous solution containing 15% to 40% of a polyhydric alcohol is subjected to autoclave sterilization to obtain a sterile aqueous suspension (Japanese Patent Laid-open No. 8-187280) have been proposed. The addition of these additive ingredients causes various problems, however, such as a decrease in absorption of the drug through the mucous membrane or induction of irritability to the mucous membrane.
On the other hand, when a sterile aqueous suspension is attempted to be obtained by sterilization by filtration, the suspension must have an appropriately low viscosity to be filtered through a 0.22 μm sterile filter. There is thus a problem that when the viscosity of a formulation is reduced, homogeneous dispersion of a water insoluble or slightly water soluble drug is deteriorated during storage over a long period of time. In this regard, an aqueous suspension from which a drug is precipitated but which has an excellent redispersibility has been proposed (Japanese Patent Laid-open No. 8-295622). There is a problem, however, that when the suspension is shaken for redispersion of a drug upon administration, entrapment of air bubbles occurs to deteriorate quantitative dispensing of the drug.